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RESEARCH HIGHLIGHTS
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
Tim-3 promotes maternal tolerance
Natural killer (NK) cells have a protective role in establishing and
maintaining maternal tolerance to a developing fetus. In Science
Signaling, Li et al. show that peripheral NK cells upregulate their
expression of the immunoinhibitory molecule Tim-3 during the
first trimester of pregnancy and thereby promote maternal–fetal
tolerance via interaction with the Tim-3 ligand galectin-9. Tim3+ NK cells express anti-inflammatory cytokines and are less
cytotoxic than Tim-3– NK cells. NK cells from women who have
experienced recurrent miscarriages have lower expression of Tim-3
protein and are more cytotoxic than NK cells obtained during a
normal pregnancy. Corresponding differences at the chromatin
level and in gene expression are also seen in Tim-3+ and Tim3– NK cells. Tim-3+ NK cells also contribute to an increased
frequency of induced regulatory T cells dependent on the
cytokine TGF-β1, which suggests another mode by which NK cells
contribute to maternal–fetal tolerance.
LAD
Sci. Signal. 10, eaa4323 (26 September 2017)
CD28 enhances mitochondrial function
Costimulation via the co-receptor CD28 is required for the generation of
effective memory T cells. A lack of CD28 signaling during the priming
of naive T cells results in anergic T cells that fail to provide protection
against subsequent challenge. In Cell, Pearce and colleagues reveal that
CD28 signals at initial priming lead to metabolic changes that result in the
increased mitochondrial morphology, spare respiratory capacity and fattyacid metabolism necessary for effector memory responses. Mechanistically,
CD28 transiently suppresses the metabolic regulator TXNIP, which
regulates expression of the microRNA miR-33. In turn, CD28 enhances
expression of the miR-33 target Cpt1a, which encodes the rate-limiting
mitochondrial enzyme carnitine palmitoyltransferase that is necessary
for fatty-acid oxidation. Modulation of miR-33 expression during T cell
priming is inversely correlated with memory-cell function after recall challenge. The Cpt1a inhibitor etomoxir likewise impairs the CD28-dependent
function of memory T cells. Thus, early CD28 signals prepare T cells for
subsequent memory responses by enhancing mitochondrial capacity and
fatty-acid utilization.
LAD
Cell (14 September 2017) doi:10.1016/j.cell.2017.08.018
What is the point of the gallbladder?
The lectin and surfactant SP-D is a secreted component of the
innate immune system known mainly for its presence and function in
the lungs. In the Proceedings of the National Academy of Sciences
USA, Taniguchi and colleagues find that SP-D is also generated
by epithelial cells in the gallbladder, but nowhere else within the
digestive system or in the liver. SP-D is secreted into the intestine
as a component of bile; once there, it binds particular commensals
such as Lactobacillus species. Deficiency in SP-D results in
dysbiosis, including a reduction in the abundance of Clostridia
species, which have been linked to the homeostasis of regulatory
T cells. SP-D-deficient mice also exhibit worse experimentally
induced colitis. The apparently unique production of SP-D within the
digestive system has potentially important implications for otherwise
routine gallbladder removal (cholecystectomy).
ZF
Proc. Natl. Acad. Sci. USA (19 Sep 2017) doi:10.1073/
pnas.1712837114
Written by Laurie A. Dempsey, Zoltan Fehervari & Ioana Visan
NATURE IMMUNOLOGY VOLUME 18 NUMBER 11 NOVEMBER 2017
Old fat macrophages
Catecholamine signaling is normal in the elderly; however, the catecholamine-induced generation of free fatty acids diminishes with age. In Nature,
Camell et al. show that adipose tissue macrophages regulate the age-dependent decrease in adipocyte lipolysis in mice by lowering the availability
of noradrenaline. Aged adipose tissue macrophages inhibit the release
of free fatty acids from noradrenaline-stimulated young adipocytes and
have high expression of enzymes that regulate catecholamine catabolism,
such as monoamine oxidase A, as well as of genes encoding molecules
linked to inflammasome activation. Aged Nlrp3–/– mice show restoration
of expression of factors involved in catecholamine catabolism and in the
release of free fatty acids after fasting, which are lower in old wild-type
mice than in young wild-type mice. Inhibition of monoamine oxidase A in
inflammasome-activated macrophages restores lipolysis in noradrenalineinduced adipocytes in vitro and fasting-induced lipolysis in old mice in vivo.
Macrophages are present in association with sympathetic nerve fibers in
the adipose tissue, which suggests that they might regulate the access of
adipocytes to noradrenaline.
IV
Nature (27 September 2017) doi:10.1038/nature23912
Breathe easy with neutrophils
The lungs are continually exposed to harmful pathogens such as
Aspergillus fumigatus, and prompt clearance of such pathogens
with limited inflammation is needed to avoid dangerous
aspergillosis or collateral damage from the immune response. In
Science, Hohl and colleagues demonstrate that myeloid cells in
the lungs, such as neutrophils, induce an apoptosis-like process
of programmed cell death (PCD) in A. fumigatus conidia. This
process is dependent on the generation of reactive oxygen species
in neutrophils via the NADPH complex. Accordingly, fungi that
overexpress the anti-apoptotic protein AfBIR1 are relatively
resistant to neutrophil-induced PCD and demonstrate enhanced
virulence. This previously unknown PCD-dependent mechanism
for the clearance of conidia represents an effective form of lung
immunosurveillance that prevents transition of the fungus to its
invasive hyphal form; additionally, it suggests a potential target for
the pharmacological treatment of fungal infection.
ZF
Science 357, 1037–1041 (2017)
Neurodegenerative signature
Microglia lose their homeostatic function during neurodegenerative disorders. In Immunity, Butovsky and colleagues show that in mouse models
of amyotrophic lateral sclerosis, Alzheimer’s disease and multiple sclerosis,
the neurodegenerative phenotype of microglia is triggered by activation of
the receptor TREM2–apolipoprotein E (APOE) pathway. This phenotype
is characterized by the suppression of TGF-β-dependent genes encoding
homeostatic molecules, such as Sall1 and Tgfbr1, and the upregulation
of genes encoding inflammatory molecules, including Apoe and Clec7a,
and is distinct from microglial activation induced by lipopolysaccharide
or the cytokine IFN-γ. The expression of APOE and Clec7a increases in
microglia situated in close proximity to amyloid-b plaques in humans
and mice and is induced by the injection of apoptotic neurons but not
by Escherichia coli or zymosan. The neurodegenerative phenotype is not
induced in Apoe–/– or Trem2–/– microglia after the phagocytosis of apoptotic neurons, and in contrast to wild-type microglia, Apoe–/– microglia
from the spinal cord of mice at the peak of experimental autoimmune
encephalomyelitis suppress T cell proliferation. As such, APOE might
inhibit a tolerogenic phenotype in microglia.
IV
Immunity 47, 566–581 (2017)
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